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Hypermut 2.0 Details

Background

Hypermut 2.0 allows searching for mutations fitting a pattern you specify. The default pattern is designed to detect hypermutation by APOBEC3G or APOBEC3F. The default pattern will not detect excess substitutions caused by an excess of adenine in PCR pools, for example. The positions that match the upstream context pattern, followed by the specified mutation (relative to the reference sequence, assumed to be the first entered, and treated as ancestral) followed by the downstream context will be found. Likewise, matches to the Control pattern will be shown for comparison. The default settings allow detection of excess APOBEC-induced hypermutation relative to control (non-APOBEC) mutations. The context requirements can be enforced on the reference sequence, or on the mutated sequence (recommended, especially if the reference is distant) or both. Normally only the contexts should differ between the control pattern and the test pattern. Fisher's exact test is then used to detect any increase of mutation for the specified context compared to the control context.

Patterns

Patterns you might want to
try are below. (Note the Upstream field is always blank here; although APOBECs do
not like an upstream C, CGs are rare enough that this does not eliminate very
many sites.) The default pattern is designed to detect hypermutation
by APOBEC3G or APOBEC3F.

For the p-values to be meaningful, the control pattern should be
a mutation that would happen with the same rate constant as the
tested mutation in the absence of hypermutation. This is roughly
true when these patterns differ only in the context positions,
and generally not true otherwise. The current program is not set up to compute valid p-values for the G→A/A→G ratio.

Mutation

Control Pattern

Upstr.

Mut.

Dnstr.

Upstr.

Mut.

Dnstr.

Application

Remarks

↓

↓

↓

↓

↓

↓

G→A

RD

G→A

YN|RC

Detect hypermutation.

The default setting.

G→A

GD

G→A

YN|RC

Detect mainly APOBEC3G hypermutation.

We have not validated this.

G→A

AD

G→A

YN|RC

Detect mainly APOBEC3F hypermutation.

We have not validated this.

G→A

A→G

Count G→A versus A→G as in original hypermut.

The p-values are not calculated for these counts because they are
not meaningful.
The tested mutation and control do not have the same change in
nucleotide content.

IUPAC Codes

As in regular expressions, the symbol ‘|’ means ‘OR’.
Thus GGT|GAA matches GGT or GAA.
() can be used for grouping, i.e., you could also write G(GT|AA).
All of the IUPAC nucleotide codes are supported:

IUPAC symbol

meaning

R

[AG] (i.e, A or G)

Y

[CT]

B

[^A] (i.e, not A)

D

[^C]

H

[^G]

V

[^T]

N

[ACGT]

W

[AT]

S

[CG]

K

[GT]

M

[AC]

For technical reasons, the upstream context pattern must
always match a fixed number of nucleotides. For example,
A|(TC) is not allowed as an upstream pattern because
it could have length 1 or 2. The same requirement
holds for the mutation pattern, which is normally just
one character anyway, but fixed length patterns (of reasonable length)
should work fine.